Zonisamide has widely been used as an antiepileptic agent in Japan and the United States. Zonisamide and processes for the preparation thereof are disclosed in JP-A-53-77057, U.S. Pat. No. 4,172,896 and JP-A-54-163823. In addition, Yakugaku-Zasshi, vol. 116, p. 533-547 (1996) discloses that zonisamide has actually been prepared using as an intermediate 1,2-benzisoxazole-3-methanesulfonyl chloride, which is obtained by sulfonation and decarboxylation of 1,2-benzisoxazol-3-acetic acid. Further, the solvent for the above sulfonation and decarboxylation is dichloromethane in the process disclosed in Yakugaku-Zasshi, vol. 116, p. 533-547 (1996), and 1,2-dichloroethane in the process disclosed in JP-A-53-77057.
The solvent used in the preparation of a drug substance cannot completely be removed by practical manufacturing techniques, which are in actuality employed in the production. Therefore, in the preparation of drug substance wherein plural steps are serially carried out till the final step, each solvent used in each step may possibly remain in a residual amount in the drug substance. Further, residual solvents in the drug substance usually cannot be useful for the therapeutic benefits of the drug substance, and contrarily, there may be caused a problem of safety of a patient according to the kinds of residual solvents and a concentration thereof. In terms of improving and increasing the safety of drugs, “IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS”, ICH Harmonized Tripartite Guideline, 17 Jul. 1997 was made in INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE (ICH).
Since a solvent may play an important role in increasing the yield rate or in determination of physical properties of drug substance such as crystal form, purity, solubility, etc., even if such a solvent is known to be toxic, there may be many cases that the use thereof in the preparation of drug substance cannot be avoided in terms of risk-benefits. In such cases, this guideline decrees that a concentration of a residual solvent in the drug substance should be not more than a limit which is toxicologically acceptable.
A solvent for the preparation of the intermediate for zonisamide, 1,2-benzisoxazole-3-methanesulfonyl chloride, is 1,2-dichloroethane rather the dichloromethane. This is because, during the decarboxylation, which is carried out after the sulfonation of 1,2-benzisoxazole-3-acetic acid, the reaction mixture requires to be heated at about 60° C., which is higher than the boiling point of dichloromethane. In addition, 1,2-dichloroethane can be used as well in the step of preparation of zonisamide by reacting 1,2-benzisoxazole-3-methanesulfonyl chloride with ammonia. However, when zonisamide is prepared using 1,2-dichloroethane, the residual concentration thereof should be not more than 5 ppm as defined in the above-mentioned guideline “IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS”. This guideline is not applied to the drugs, which are already on market, but it is very important to prepare a drug substance complying with this guideline in terms of safety of drugs.
The removal of residual solvent is usually carried out by drying. However, it is very difficult to completely remove an occluded solvent by a drying method being actually employed in the production. U.S. Pat. No. 4,533,746 discloses a method of removing the solvent by distillation in purification of bisphenols, wherein the solvent occluded in bisphenols is released and removed from bisphenol melted in water. This method utilizes the characteristic of bisphenol, which melts in water by heating, and thereby the occluded solvent is released. On the other hand, zonisamide cannot melt even by heating in water, and hence, this method cannot be applied for removal of the solvent occluded in crystals of zonisamide.